A Phase I Open-Label Study of Single and Repeated Doses of Intravitreal JSM6427, a Small Molecule Integrin 5β1 Antagonist, in Neovascular Age-Related Macular Degeneration (AMD)

Abstract

Purpose: : To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose of single and multiple doses of intravitreal JSM6427 in patients with neovascular AMD.

Methods: : JSM6427 is a specific, highly potent, small molecule antagonist of integrin α₅β₁ (the fibronectin receptor), part of a final common downstream pathway for multiple angiogenic growth factors that is involved in developmental and adult angiogenesis. In pre-clinical models, JSM6427 has been shown to inhibit the development of new choroidal neovascularization (CNV), cause regression of established CNV, and inhibit inflammation and fibrosis, making α₅β₁ an attractive target for therapeutic strategies directed at the treatment as well as the prevention of pathologic angiogenesis.The current phase I, open-label, first-in-human, dose-escalation study includes patients with subfoveal AMD with ≥ 25% active choroidal neovascularization, center point thickness ≥ 250 µm by optical coherence tomography (OCT), and best corrected visual acuity (BCVA) by ETDRS of 20/40 - 20/800. Prior therapy for neovascular AMD is allowed after appropriate wash-out periods. Patients receive up to four intravitreal injections of JSM6427 and are followed for safety and efficacy with BCVA, OCT, fundus photography, ERG, fluorescein angiography, and detailed eye exams for 52 weeks.

Results: : In the first single-dose cohort of patients, all of whom were previously treated with multiple intravitreal injections of anti-VEGF therapies, there have been no signs of toxicity to date. In early follow-up, BCVA by ETDRS was unchanged or improved in all patients with a mean change of +3.3 letters while the OCT central subfield was decreased by a mean of -25.3 µm.

Conclusions: : Single intravitreal injections of low-dose JSM6427 are well tolerated in patients with neovascular AMD. Due to the known short vitreous half-life of the current formulation, higher single doses as well as repeated doses are being studied and updated data will be presented. In addition a sustained-release formulation is in development for the prevention as well as the treatment of neovascular AMD.

Clinical Trial: : www.clinicaltrials.gov NCT00536016

Keywords: age-related macular degeneration • choroid: neovascularization • inflammation